The association of C3435T single-nucleotide polymorphism, Pgp-glycoprotein gene expression levels and carbamazepine maintenance dose in patients with epilepsy

The ABCB1 gene encodes the P-glycoprotein (Pgp) protein, which is thought to transport various antiepileptic drugs. The single nucleotide polymorphism (SNP) (C3435T) in exon 26 of this gene correlates with the altered expression levels of P-glycoprotein, range of drug response and clinical conditions. In order to investigate the influence of this polymorphism on the susceptibility to and efficacy of carbamazepine therapy, we evaluated the allelic frequency and genotype distribution of this variant in 162 epilepsy patients from the Republic of Macedonia. Statistically significant differences were detected neither in the allelic frequency and genotype distribution between carbamazepine-resistant and carbamazepine-responsive epilepsy patients nor between the subgroups of carbamazepine (CBZ)-responsive patients treated with different CBZ doses. However, the T-allele was enriched in CBZ-responsive patients who required higher maintenance CBZ doses, This observation was substantiated by the findings that the median total plasma levels were the lowest in patients with CC (20 μmol/L) followed by CT (23 μmol/L) and TT (29 μmol/L) genotypes. Patients with a CC genotype also had a higher likelihood of response compared to patients with CT or TT genotypes over a wide range (400–1000 mg/day) of initial doses of CBZ. The T allele showed a reduced expression of ~5% compared to the C allele in peripheral blood mononuclear cells in heterozygotes for the variant. This difference might be translated into ~10% difference in homozygotes for the variant, which would explain the trend towards a dose-dependent efficacy of the CBZ treatment in patients with different genotypes. A larger prospective study is warranted to clarify the clinical utility of a genotypespecific individualized CBZ therapy

More Scalable LTL Model Checking via Discovering Design-Space Dependencies (D3)

Modern system design often requires comparing several models over a large design space. Different models arise out of a need to weigh different design choices, to check core capabilities of versions with varying features, or to analyze a future version against previous ones. Model checking can compare different models; however, applying model checking off-the-shelf may not scale due to the large size of the design space for today’s complex systems. We exploit relationships between different models of the same (or related) systems to optimize the model-checking search. Our algorithm, D3 , preprocesses the design space and checks fewer model-checking instances, e.g., using nuXmv. It automatically prunes the search space by reducing both the number of models to check, and the number of LTL properties that need to be checked for each model in order to provide the complete model-checking verdict for every individual model-property pair. We formalize heuristics that improve the performance of D3 . We demonstrate the scalability of D3 by extensive experimental evaluation, e.g., by checking 1,620 real-life models for NASA’s NextGen air traffic control system. Compared to checking each model-property pair individually, D3 is up to 9.4 × faster

Management earnings forecasts and IPO performance: evidence of a regime change

Companies undertaking initial public offerings (IPOs) in Greece were obliged to include next-year profit forecast in their prospectuses, until the regulation changed in 2001 to voluntary forecasting. Drawing evidence from IPOs issued in the period 1993–2015, this is the first study to investigate the effect of disclosure regime on management earnings forecasts and IPO long-term performance. The findings show mainly positive forecast errors (forecasts are lower than actual earnings) and higher long-term returns during the mandatory period, suggesting that the mandatory disclosure requirement causes issuers to systematically bias profit forecasts downwards as they opt for the safety of accounting conservatism. The mandatory disclosure requirement artificially improves IPO share performance. Overall, our results show that mandatory disclosure of earnings forecasts can impede capital market efficiency once it goes beyond historical financial information to involve compulsory projections of future performance

Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi identifies inter- and intracontinental transmission events.

The emergence of multidrug-resistant (MDR) typhoid is a major global health threat affecting many countries where the disease is endemic. Here whole-genome sequence analysis of 1,832 Salmonella enterica serovar Typhi (S. Typhi) identifies a single dominant MDR lineage, H58, that has emerged and spread throughout Asia and Africa over the last 30 years. Our analysis identifies numerous transmissions of H58, including multiple transfers from Asia to Africa and an ongoing, unrecognized MDR epidemic within Africa itself. Notably, our analysis indicates that H58 lineages are displacing antibiotic-sensitive isolates, transforming the global population structure of this pathogen. H58 isolates can harbor a complex MDR element residing either on transmissible IncHI1 plasmids or within multiple chromosomal integration sites. We also identify new mutations that define the H58 lineage. This phylogeographical analysis provides a framework to facilitate global management of MDR typhoid and is applicable to similar MDR lineages emerging in other bacterial species

An extended genotyping framework for Salmonella enterica serovar Typhi, the cause of human typhoid.

The population of Salmonella enterica serovar Typhi (S. Typhi), the causative agent of typhoid fever, exhibits limited DNA sequence variation, which complicates efforts to rationally discriminate individual isolates. Here we utilize data from whole-genome sequences (WGS) of nearly 2,000 isolates sourced from over 60 countries to generate a robust genotyping scheme that is phylogenetically informative and compatible with a range of assays. These data show that, with the exception of the rapidly disseminating H58 subclade (now designated genotype 4.3.1), the global S. Typhi population is highly structured and includes dozens of subclades that display geographical restriction. The genotyping approach presented here can be used to interrogate local S. Typhi populations and help identify recent introductions of S. Typhi into new or previously endemic locations, providing information on their likely geographical source. This approach can be used to classify clinical isolates and provides a universal framework for further experimental investigations

Pathogen survival in portioned retail soft cheeses

C1 - Journal Articles Referee